Irradiation stent with 125 I plus TACE versus sorafenib plus TACE for hepatocellular carcinoma with major portal vein tumor thrombosis: a multicenter randomized trial.

BACKGROUND AND AIM: Treatment strategy for hepatocellular carcinoma (HCC) and Vp4 [main trunk] portal vein tumor thrombosis (PVTT) remains limited due to posttreatment liver failure. We aimed to assess the efficacy of irradiation stent placement with 125 I plus transcatheter arterial chemoembolization (TACE) (ISP-TACE) compared to sorafenib plus TACE (Sora-TACE) in these patients. METHODS: In this multicenter randomized controlled trial, participants with HCC and Vp4 PVTT without extrahepatic metastases were enrolled from November 2018 to July 2021 at 16 medical centers. The primary endpoint was overall survival (OS). The secondary endpoints were hepatic function, time to symptomatic progression, patency of portal vein, disease control rate, and treatment safety. RESULTS: Of 105 randomized participants, 51 were assigned to the ISP-TACE group, and 54 were assigned to the Sora-TACE group. The median OS was 9.9 months versus 6.3 months (95% CI: 0.27-0.82; P =0.01). Incidence of acute hepatic decompensation was 16% (8 of 51) versus 33% (18 of 54) ( P =0.036). The time to symptomatic progression was 6.6 months versus 4.2 months (95% CI: 0.38-0.93; P =0.037). The median stent patency was 7.2 months (interquartile range, 4.7-9.3) in the ISP-TACE group. The disease control rate was 86% (44 of 51) versus 67% (36 of 54) ( P =0.018). Incidences of adverse events at least grade 3 were comparable between the safety populations of the two groups: 16 of 49 (33%) versus 18 of 50 (36%) ( P =0.73). CONCLUSION: Irradiation stent placement plus TACE showed superior results compared with sorafenib plus TACE in prolonging OS in patients with HCC and Vp4 PVTT.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Multiple primary malignancies - hepatocellular carcinoma combined with splenic lymphoma: A case report.

BACKGROUND: Primary liver cancer is one of the most common malignant tumours, while primary splenic lymphoma is a rare malignancy. Thus, cases of hepatocellular carcinoma (HCC) combined with splenic lymphoma are extremely rare. CASE SUMMARY: We present a 62-year-old woman who was admitted to the Interventional Radiology Department with a lump in the spleen and liver as well as multiple enlarged lymph nodes visible by ultrasound. Contrast-enhanced computed of the abdomen revealed a circular, low-density, shallow mass (approximately 2.6 cm in diameter) in the left intrahepatic lobe and multiple round, low-density shadows in the spleen with clear boundaries (maximum diameter 7.6 cm). Based on the characteristic clinical symptoms and explicit radiological findings, the clinical diagnosis was HCC with metastasis to the liver portal, retroperitoneal lymph nodes, and spleen. After transcatheter arterial chemoembolization and sequential radiofrequency ablation, the -fetoprotein level returned to the normal range, and the hepatitis B cirrhosis improved. In addition, splenic tumour biopsy confirmed the diagnosis of primary malignant lymphoma, which went into remission after chemotherapy. CONCLUSION: HCC with primary splenic non-Hodgkin lymphoma is extremely rare and easily misdiagnosed. Better understanding would facilitate early diagnosis, treatment and prognosis.

A role for the NPM1/PTPN14/YAP axis in mediating hypoxia-induced chemoresistance to sorafenib in hepatocellular carcinoma.

BACKGROUND: Tumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy. Hypoxia plays an important role in the development of tumor resistance, as well as the generation of metastatic potential. YAP also participates in the regulation of hypoxia-mediated chemoresistance, and is negatively regulated by protein tyrosine phosphatase non-receptor type 14 (PTPN14). METHODS: The PTPN14 expression in hepatocellular carcinoma (HCC) tissues were evaluated by qRT-PCR, western blot and tissue microarrays. The effect of PTPN14 on HCC progression was investigated in vitro and in vivo. RESULTS: Here, we report that PTPN14 expression was downregulated in HCC tissues and cell lines. Silencing PTPN14 significantly enhanced proliferation, migration, invasion of HepG2 cells in vitro and tumor growth and metastasis in vivo, whereas overexpression of PTPN14 significantly inhibited these abilities in SK-Hep1 cells. We also found that hypoxia-induced nuclear translocation and accumulation of PTPN14 led to resistance to sorafenib in HCC cells. Further mechanistic studies suggested that NPM1 regulates PTPN14 localization, and that NPM1 regulates YAP by retaining PTPN14 in the nucleus under hypoxic conditions. CONCLUSIONS: These data suggest that a therapeutic strategy against chemoresistant HCC may involve disruption of NPM1-mediated regulation of YAP by retaining PTPN14 in the nucleus under hypoxic conditions.

Construction of a novel radiomics nomogram for the prediction of aggressive intrasegmental recurrence of HCC after radiofrequency ablation.

OBJECTIVES: To construct a precise prediction model of preoperative magnetic resonance imaging (MRI)-based nomogram for aggressive intrasegmental recurrence (AIR) of hepatocellular carcinoma (HCC) patients treated with radiofrequency ablation (RFA). METHODS: Among 891 patients with HCC treated by RFA, 22 patients with AIR and 36 patients without AIR (non-AIR) were finally enrolled in our study, and each patient was followed up for more than 6 months to determine the occurrence of AIR. The laboratory indicators and MRI features were compared and assessed. Preoperative contrast-enhanced T1-weighted images (CE-T1WI) were used for radiomics analysis. The selected clinical indicators and texture features were finally screened out to generate the novel prediction nomogram. RESULTS: Tumor shape, ADC Value, DWI signal intensity and ΔSI were selected as the independent factors of AIR by univariate and multivariate logistic regression analysis. Meanwhile, two radiomics features were selected from 396 candidate features by LASSO (P < 0.05), which were further used to calculate the Rad-score. The selected clinical factors were further integrated with the Rad-score to construct the predictive model, and the AUCs were 0.941 (95% CI: 0.876-1.000) and 0.818 (95% CI: 0.576-1.000) in the training (15 AIR and 25 non-AIR) and validation cohorts (7 AIR and 11 non-AIR), respectively. The AIR predictive model was further converted into a novel radiomics nomogram, and decision curve analysis showed good agreement. CONCLUSIONS: The predictive nomogram integrated with clinical factors and CE-T1WI -based radiomics signature could accurately predict the occurrence of AIR after RFA, which could greatly help individualized evaluation before treatment.

A Radiomics Signature-Based Nomogram to Predict the Progression-Free Survival of Patients With Hepatocellular Carcinoma After Transcatheter Arterial Chemoembolization Plus Radiofrequency Ablation.

Objective: The study aims to establish an magnetic resonance imaging radiomics signature-based nomogram for predicting the progression-free survival of intermediate and advanced hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation Materials and Methods: A total of 113 intermediate and advanced HCC patients treated with TACE and RFA were eligible for this study. Patients were classified into a training cohort (n = 78 cases) and a validation cohort (n = 35 cases). Radiomics features were extracted from contrast-enhanced T1W images by analysis kit software. Dimension reduction was conducted to select optimal features using the least absolute shrinkage and selection operator (LASSO). A rad-score was calculated and used to classify the patients into high-risk and low-risk groups and further integrated into multivariate Cox analysis. Two prediction models based on radiomics signature combined with or without clinical factors and a clinical model based on clinical factors were developed. A nomogram comcined radiomics signature and clinical factors were established and the concordance index (C-index) was used for measuring discrimination ability of the model, calibration curve was used for measuring calibration ability, and decision curve and clinical impact curve are used for measuring clinical utility. Results: Eight radiomics features were selected by LASSO, and the cut-off of the Rad-score was 1.62. The C-index of the radiomics signature for PFS was 0.646 (95%: 0.582-0.71) in the training cohort and 0.669 (95% CI:0.572-0.766) in validation cohort. The median PFS of the low-risk group [30.4 (95% CI: 19.41-41.38)] months was higher than that of the high-risk group [8.1 (95% CI: 4.41-11.79)] months in the training cohort (log rank test, z = 16.58, p < 0.001) and was verified in the validation cohort. Multivariate Cox analysis showed that BCLC stage [hazard ratio (HR): 2.52, 95% CI: 1.42-4.47, p = 0.002], AFP level (HR: 2.01, 95% CI: 1.01-3.99 p = 0.046), time interval (HR: 0.48, 95% CI: 0.26-0.87, p = 0.016) and radiomics signature (HR 2.98, 95% CI: 1.60-5.51, p = 0.001) were independent prognostic factors of PFS in the training cohort. The C-index of the combined model in the training cohort was higher than that of clinical model for PFS prediction [0.722 (95% CI: 0.657-0.786) vs. 0.669 (95% CI: 0.657-0.786), p＜0.001]. Similarly, The C-index of the combined model in the validation cohort, was higher than that of clinical model [0.821 (95% CI: 0.726-0.915) vs. 0.76 (95% CI: 0.667-0.851), p = 0.004]. The calibration curve, decision curve and clinical impact curve showed that the nomogram can be used to accurately predict the PFS of patients. Conclusion: The radiomics signature was a prognostic risk factor, and a nomogram combined radiomics and clinical factors acts as a new strategy for predicted the PFS of intermediate and advanced HCC treated with TACE plus RFA.

USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bß via deubiquitinating EGLN3.

BACKGROUND: Cholangiocarcinoma represents the second most common primary liver malignancy. The incidence rate has constantly increased over the last decades. Cholangiocarcinoma silent nature limits early diagnosis and prevents efficient treatment. METHODS: Immunoblotting and immunohistochemistry were used to assess the expression profiling of USP9X and EGLN3 in cholangiocarcinoma patients. ShRNA was used to silence gene expression. Cell apoptosis, cell cycle, CCK8, clone formation, shRNA interference and xenograft mouse model were used to explore biological function of USP9X and EGLN3. The underlying molecular mechanism of USP9X in cholangiocarcinoma was determined by immunoblotting, co-immunoprecipitation and quantitative real time PCR (qPCR). RESULTS: Here we demonstrated that USP9X is downregulated in cholangiocarcinoma which contributes to tumorigenesis. The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo. Clinical data demonstrated that expression levels of USP9X were positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that USP9X was involved in the deubiquitination of EGLN3, a member of 2-oxoglutarate and iron-dependent dioxygenases. USP9X elicited tumor suppressor role by preventing degradation of EGLN3. Importantly, knockdown of EGLN3 impaired USP9X-mediated suppression of proliferation. USP9X positively regulated the expression level of apoptosis pathway genes de through EGLN3 thus involved in apoptosis of cholangiocarcinoma. CONCLUSION: These findings help to understand that USP9X alleviates the malignant potential of cholangiocarcinoma through upregulation of EGLN3. Consequently, we provide novel insight into that USP9X is a potential biomarker or serves as a therapeutic or diagnostic target for cholangiocarcinoma.

Corrigendum: LncRNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway.

[This corrects the article DOI: 10.3389/fonc.2020.605877.].

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

BACKGROUND & AIMS: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD. METHODS: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination. RESULTS: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8-28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained. CONCLUSIONS: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD. LAY SUMMARY: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.

LncRNA-SNHG6 promotes the progression of hepatocellular carcinoma by targeting miR-6509-5p and HIF1A.

BACKGROUND: Accumulating evidences have been reported that long noncoding RNAs play crucial roles in the progression of hepatocellular carcinoma (HCC). SnoRNA host gene 6 (SNHG6) is believed to be involved in several human cancers, but the specific molecular mechanism of SNHG6 in HCC is not well studied. METHODS: In this study, we experimentally down-regulated the SNHG6 in two hepatocellular carcinoma cell lines in vitro, and then measured the proliferation, migration and invasion abilities and the apoptotic levels. Also, we performed the xenograft assay to investigate the function of SNHG6 during the tumor growth in vivo. RESULTS: We found SNHG6 was highly expressed in HCC tissues. Next, using Hep3B and Huh7 cells, we confirmed knockdown of SNHG6 reduced the proliferation, migration and invasion abilities in vitro. Also, by bioinformatics analysis, further molecular and cellular experiments, we found miR-6509-5p bound to SNHG6 directly, and the expression level of HIF1A was regulated through SNHG6/miR-6509-5p axis. Finally, we found that down-regulation of SNHG6 dramatically reduced the tumor growth ability of Huh7 cells in vivo. CONCLUSIONS: We concluded that SNHG6/miR-6509-5p/HIF1A axis functioned in the progression of hepatocellular carcinoma, and could be the promising therapeutic targets during the development of hepatocellular carcinoma drugs.

Sialic acid-engineered mesoporous polydopamine dual loaded with ferritin gene and SPIO for achieving endogenous and exogenous synergistic T2-weighted magnetic resonance imaging of HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis. Magnetic resonance imaging (MRI) is one of the most effective imaging methods for the early diagnosis of HCC. However, the current MR contrast agents are still facing challenges in the early diagnosis of HCC due to their relatively low sensitivity and biosafety. Thus, the development of effective MR agents is highly needed for the early diagnosis of HCC. RESULTS: Herein, we fabricated an HCC-targeted nanocomplexes containing SPIO-loaded mesoporous polydopamine (MPDA@SPIO), sialic acid (SA)-modified polyethyleneimine (SA-PEI), and alpha-fetoprotein regulated ferritin gene (AFP-Fth) which was developed for the early diagnosis of HCC. It was found that the prepared nanocomplexes (MPDA@SPIO/SA-PEI/AFP-Fth) has an excellent biocompatibility towards the liver cells. In vivo and in vivo studies revealed that the transfection of AFP-Fth gene in hepatic cells significantly upregulated the expression level of ferritin, thereby resulting in an enhanced contrast on T2-weighted images via the formed endogenous MR contrast. CONCLUSIONS: The results suggested that MPDA@SPIO/SA-PEI/AFP-Fth had a superior ability to enhance the MR contrast of T2-weighted images of tumor region than the other preparations, which was due to its HCC-targeted ability and the combined T2 contrast effect of endogenous ferritin and exogenous SPIO. Our study proved that MPDA@SPIO/SA-PEI/AFP-Fth nanocomplexes could be used as an effective MR contrast agent to detect HCC in the early stage.

Iodine-125 Brachytherapy Can Prolong Progression-Free Survival of Patients with Locoregional Recurrence and/or Residual Hepatocellular Carcinoma After Radiofrequency Ablation.

Background: Radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) is limited by locoregional recurrence and/or residual tumors caused by incomplete ablation. Iodine-125 (125I) brachytherapy can achieve a high local control rate in solid carcinoma, but few studies have assessed the efficacy of this treatment for locoregional recurrence and/or residual HCC after RFA. Objective: To investigate the effectiveness and safety of 125I brachytherapy for treating locoregional recurrence and/or residual HCC in patients treated with RFA. Methods: Eligible study patients were those with locoregional recurrence and/or residual HCC on abdominal imaging performed 1 month after RFA at this institution between February 2009 and September 2014 retrospectively. Patients were divided into either the control group (no treatment until the tumor progressed) or the treatment group (underwent 125I brachytherapy). Progression-free survival (PFS), overall survival (OS), and complications of 125I brachytherapy were evaluated. Results: A total of 42 patients were included in the final analysis, including 29 in the control group and 13 in the treatment group. A total of 457 125I particles were used (mean 32.8 ± 21.3 mCi per case). The median follow-up time was 25 months. Median PFS was 9 months in the control group and 18 months in the treatment group (p = 0.026). The median OS was 28 months in the control group and 33 months in the treatment group (p = 0.441). There were no major complications observed in patients treated with 125I brachytherapy. Conclusion: Iodine-125 brachytherapy can prolong PFS in patients with locoregional recurrence and/or residual HCC after RFA.

Multifunctional Microspheres Dual-Loaded with Doxorubicin and Sodium Bicarbonate Nanoparticles to Introduce Synergistic Trimodal Interventional Therapy.

Lactic acid in the tumor microenvironment is highly correlated with the prognosis of tumor chemoembolization, but there are limited clinical strategies to deal with it. To improve the efficacy, NaHCO3 nanoparticles are innovatively introduced into drug-loaded microspheres to neutralize lactic acid in the tumor microenvironment. Here we showed that multifunctional ethyl cellulose microspheres dual-loaded with doxorubicin (DOX) and NaHCO3 nanoparticles (DOX/NaHCO3-MS) presented excellent antitumor effects by improving the pH of the tumor microenvironment. The homeostasis of the tumor microenvironment was continuously disturbed due to the sustained release of NaHCO3 nanoparticles, which also led to a significant increase in tumor cell apoptosis (compared with the control and DOX-MS groups). We also showed that the administration of DOX/NaHCO3-MS via the hepatic artery in a rabbit model of VX2 orthotopic liver cancer resulted in optimal antitumor efficacy, and the area of tumor necrosis at the embolization site was significantly increased and the proliferation of tumor cells was significantly weakened. The designed DOX/NaHCO3-MS exhibited strong synergistic antitumor effects of embolization, chemotherapy, and tumor microenvironment improvement. The present microspheres provided a strategy for the enhancement of the chemoembolization of hepatocellular carcinoma, which could also be extended to other clinical embolization treatments for blood-rich solid tumors.

Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression.

Hepatocellular carcinoma (HCC) is one of the most lethal cancer types with insufficient approved therapies, among which lenvatinib is a newly approved multi-targeted tyrosine kinase inhibitor for frontline advanced HCC treatment. However, resistance to lenvatinib has been reported in HCC treatment recently, which limits the clinical benefits of lenvatinib. This study aims to investigate the underlying mechanism of lenvatinib resistance and explore the potential drug to improve the treatment for lenvatinib-resistant (LR) HCC. Here, we developed two human LR HCC cell lines by culturing with long-term exposure to lenvatinib. Results showed that the vascular endothelial growth factor receptors (VEGFR)2 expression and its downstream RAS/MEK/ERK signalling were obviously up-regulated in LR HCC cells, whereas the expression of VEGFR1, VEGFR3, FGFR1-4 and PDGFRα/ß showed no difference. Furthermore, ETS-1 was identified to be responsible for VEGFR2 mediated lenvatinib resistance. The cell models were further used to explore the potential strategies for restoration of sensitivity of lenvatinib. Sophoridine, an alkaloid extraction, inhibited the proliferation, colony formation, cell migration and increased apoptosis of LR HCC cells. In vivo and in vitro results showed Sophoridine could further sensitize the therapeutic of lenvatinib against LR HCC. Mechanism studies revealed that Sophoridine decreased ETS-1 expression to down-regulate VEGFR2 expression along with downstream RAS/MEK/ERK axis in LR HCC cells. Hence, our study revealed that up-regulated VEGFR2 expression could be a predicator of the resistance of lenvatinib treatment against HCC and provided a potential candidate to restore the sensitivity of lenvatinib for HCC treatment.

Oxysophocarpine suppresses FGFR1-overexpressed hepatocellular carcinoma growth and sensitizes the therapeutic effect of lenvatinib.

AIMS: Hepatocellular carcinoma (HCC) is an aggressive solid tumor with restricted therapeutics. Lenvatinib is the second approved frontline drug for advanced HCC, however lenvatinib-resistant cases have been reported in clinical. Overexpression of fibroblast growth factor receptor (FGFR1) has been found to be associated with advanced HCC. This study was aimed to investigate the relationship between FGFR1 overexpression and lenvatinib resistance, and explore the potential candidate that can sensitize lenvatinib against FGFR1-overexpressed HCC. MAIN METHODS: Development of FGFR1 overexpression was accomplished in Hep3B and HepG2 cell lines by pCDH-FGFR1 lentiviral vector. In vitro, cell proliferation, colony formation, cell migration and cell apoptosis assays were used to explore the effect of lenvatinib and Oxysophocarpine. In vivo, BALB/c nude mice were burdened with subcutaneous FGFR1-overexpressed Hep3B tumor to assess the therapeutic effect of lenvatinib and Oxysophocarpine. qRT-PCR and western blotting were further used to identify the underlying mechanism. KEY FINDINGS: Here, we revealed that overexpressed FGFR1 and its downstream AKT/mTOR and ERK signaling activation could induce lenvatinib resistance in HCC. In vivo and in vitro results showed Oxysophocarpine inhibited the proliferation and induced the apoptosis of FGFR1-overexpressed HCC cells. Oxysophocarpine could further sensitize FGFR1-overexpressed HCC cells to lenvatinib treatment. Mechanism studies revealed that Oxysophocarpine downregulated FGFR1 expression along with downstream AKT/mTOR and ERK signaling to sensitize lenvatinib against FGFR1-overexpressed HCC. SIGNIFICANCES: These data collectively provided evidence that FGFR1 overexpression could be a potential cause of lenvatinib resistance and Oxysophocarpine could be an ideal combined therapy with lenvatinib in HCC treatment.

CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway.

BACKGROUND: Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. METHODS: The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. RESULTS: In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. CONCLUSION: The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

Therapeutic Potential of Triptolide as an Anti-Inflammatory Agent in Dextran Sulfate Sodium-Induced Murine Experimental Colitis.

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic and incurable inflammatory diseases involving the gastrointestinal tract. In this study, we investigated the anti-inflammatory effects of triptolide in a dextran sulfate sodium (DSS)-induced mouse colitis model and LPS-activated macrophages and explored the specific molecular mechanism(s). In mice, triptolide treatment showed significant relief and protection against colitis, and it markedly reduced the inflammatory responses of human monocytes and mouse macrophages. Pharmacological analysis and weighted gene co-expression network analysis (WGCNA) suggested that PDE4B may be an important potential targeting molecule for IBD. Exploration of the specific mechanism of action indicated that triptolide reduced the production of ROS, inhibited macrophage infiltration and M1-type polarization by activating the NRF2/HO-1 signaling pathway, and inhibited the PDE4B/AKT/NF-κB signaling cascade, which may help weaken the intestinal inflammatory response. Our findings laid a theoretical foundation for triptolide as a treatment for IBD and revealed PDE4B as a target molecule, thus providing new ideas for the treatment of IBD.

The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma.

BACKGROUND: In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. METHODS: Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes. RESULTS: Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy. CONCLUSIONS: The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Video Abstract.

The Effect of m6A Methylation Regulatory Factors on the Malignant Progression and Clinical Prognosis of Hepatocellular Carcinoma.

The modification level of the transcript N6-methyladenosine (m6A), dynamically regulated by methyltransferases, binding proteins and demethylases, is closely related to the occurrence, and progression of tumors. Here, 13 differentially expressed m6A methylation regulators were confirmed in 374 hepatocellular carcinoma (HCC) patients, among which RBM15, YTHDC1, YTHDF1, and YTHDF2 were significantly variant in different stages and grades. Further consensus clustering analysis identified two HCC subtypes (cluster1/2) in this cohort, finding an active role of the m6A methylation regulators in the malignant progression of HCC. Furthermore, GESA enrichment analysis showed that PPAR signaling pathway, and the pathways involved in retinol metabolism and peroxisome were related to tumor progression. Additionally, a 4-gene risk model (ROC = 0.729) that can be used as a prognostic marker and a predictor for clinicopathological characteristics of HCC was constructed via univariate and multivariate Cox regression analyses. Analysis on overall survival and disease-free survival demonstrated that METTL3 and YTHDF1 out of the four genes in the model could serve as independent prognostic factors for HCC. Overall, this study systematically investigated the effect of m6A methylation regulators on the malignant progression of HCC and proposed a 4-gene risk prediction model, laying a theoretical foundation for the further research on HCC prognosis.